Summary: In the United States, 20.8 million people suffer from diabetes. About 176,500 people under 20 years of age have diabetes. About 75% of all newly diagnosed cases of type I diabetes occurs in individuals younger than 18 years of age. People with Type1diabetes must take daily insulin injections to stay alive. Frequent injection of insulin is required for the treatment of all patients with type I and many patients with type II diabetes. In healthy individuals, basal insulin is secreted continuously between meals and throughout the night at a rate of 0.5-1 Unit/h. Although the basal insulin level is low, it modulates the rate of overnight hepatic glucose and glucose output during prolonged periods between meals. This allows for sufficient glucose level for cerebral energy production at bedtime. Injectable polymeric delivery systems can be used for continuous release of insulin to meet the need of basal insulin for a desired period. The long-term goal of this work is to develop controlled release formulations which can deliver insulin continuously in a conformationally as well as chemically stable and biologically active form for longer duration after a single injection. We propose to test the hypotheses that the temperature sensitive biodegradable polymers can control the in vitro and in vivo release of insulin in biologically active, conformationally and chemically stable form and the proposed polymer-based delivery systems are biocompatible. To test our hypotheses, we plan to study the following specific aims:[1].To synthesize temperature sensitive triblock copolymers and characterize their critical gel concentration, gel transition temperature, weight average molecular weight by gel permeation chromatography, and number average molecular weight by H NMR. [2]. To prepare in situ gel-forming controlled delivery systems for insulin, using temperature sensitive polymers. [3]. To study in vitro release profiles of insulin from the delivery systems and to evaluate factors that can affect the release. [4].To evaluate the chemical stability of released insulin using HPLC-MS technique. [5]. To evaluate the conformational stability of released insulin by differential scanning calorimetry (DSC). [6]. To evaluate the in vitro and in vivo biocompatibility of the delivery systems by MTT assay and histological analysis using light microscopy, respectively. [7]. To study in vivo absorption and bioactivity of insulin from the delivery systems in diabetic rats. The proposed study will contribute significantly to the development of an injectable form which delivers insulin at a controlled rate for longer duration (~ 2 months) after a single injection. Development of such a delivery system will improve patients' quality of life, and decrease the long term complications associated with diabetes. The proposed efforts will contribute significantly for the development of polymer solution based delivery systems to deliver insulin at a controlled rate for longer duration after single subcutaneous injection. Development of such a novel therapeutic system is critical for successful treatment of diabetes and improvement in the patients' quality of life. [unreadable] [unreadable] [unreadable]